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OFD1 – X-linked Retinitis Pigmentosa 23

OFD1 – X-linked Retinitis Pigmentosa 23 is an X-linked recessive retinal degenerative disorder caused by a hypomorphic intronic variant in OFD1. Targeted next-generation sequencing of the RP23 locus identified a deep intronic mutation, c.935+706A>G, which creates a novel splice donor 4 bp upstream of the variant, leading to insertion of a cryptic exon between exons 9 and 10. This insertion introduces a frameshift (p.Asn313fsTer330) and reduces correctly spliced OFD1 transcript levels to 39% in patient-derived RNA ([PMID:22619378]). No coding or canonical splice site variants were identified, and segregation beyond the index family has not been reported. Functional in vivo RNA assays confirm partial loss of function, demonstrating that photoreceptors are uniquely sensitive to reduced OFD1 dosage, implicating a dosage-dependent ciliopathy mechanism. Although based on a single kindred, these data reveal a novel hypomorphic allele linking OFD1 to isolated retinitis pigmentosa rather than syndromic ciliopathy.

References

  • Human molecular genetics • 2012 • Deep intronic mutation in OFD1, identified by targeted genomic next-generation sequencing, causes a severe form of X-linked retinitis pigmentosa (RP23). PMID:22619378

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Single deep intronic OFD1 variant identified in one RP23 family with a single proband ([PMID:22619378]); no additional segregation data.

Genetic Evidence

Limited

One intronic variant (c.935+706A>G) in OFD1 detected by targeted sequencing in a single kindred; no further family segregation ([PMID:22619378]).

Functional Evidence

Moderate

In vivo RNA assays demonstrate cryptic exon insertion, frameshift p.Asn313fsTer330, and residual wild-type transcript levels (39%), supporting a hypomorphic loss-of-function mechanism ([PMID:22619378]).